Two decades ago it was reported that atherosclerotic arteries produce more 15-HETE as compared to normal arteries. The work in our laboratory showed that vascular smooth muscle cells (VSMC) upon exposure to arachidonic acid produce 15(S)-HETE as a major LOX product. In addition, our preliminary results revealed that 15(S)-HETE stimulates VSMC motility more potently than 5(S)-HETE or 12(S)-HETE. Most importantly, 15(S)-HETE induced the expression of monocyte chemotactic protein-1 (MCP-1). Based on these exciting findings, we hypothesized that 15(S)-HETE by inducing the expression of MCP-1 stimulates VSMC motility and thereby plays a major role in vascular wall remodeling in response to injury. To prove this hypothesis, we will test the following four specific aims: [unreadable] [unreadable] Specific Aim 1: 15(S)-HETE stimulates VSMC motility by induction of expression of MCP-1 via activation of Src. Specific Aim 2: Activation of mitogen-activated protein kinase (MAPK) cascades and activator protein-1 (AP-1) is required for 15(S)-HETE-induced MCP-1 expression and VSMC motility. Specific Aim 3: The Janus-activated kinase (Jak)/signal transducer and activator of transcription (STAT) pathway mediates 15(S)-HETE-induced VSMC motility via induction of expression of MCP-1. Specific Aim 4: Overexpression of 15-LOX1/2 exacerbates injury-induced neointima formation via production of 15(S)-HETE and thereby in the enhancement of SMC migration from media to intima and recruitment of bone marrow cells to the site vascular injury. [unreadable] [unreadable] By executing the experiments proposed in the above four specific aims involving state of the art cell and molecular biological techniques, we expect to address how 15(S)-HETE could play a role in vascular wall remodeling in response to injury. Therefore, the findings of this research proposal would enhance our understanding on the role of eicosanoids in vacular wall remodeling and thereby in the development of potential therapeutics against proliferative cardiovascular diseases such as restenosis following angioplasty. Motility and growth of vascular smooth muscle cells play a major role in proliferative cardiovascular diseases such as restenosis following angioplasty. Understanding the mechanisms underlying these cellular events is crucial in the development of therapeutic agents against these vascular lesions. The present research proposal seeks to study the role of eicosanoids in vascular wall remodeling in response to injury. [unreadable] [unreadable] [unreadable]